Asymmetric synthesis,molecular modeling and biological evaluation of 5-methyl-3-aryloxazolidine-2,4-dione enantiomers as monoamine oxidase (MAO) inhibitors |
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| Affiliation: | 1. Bogazici University, Department of Chemistry, Bebek, 34342 Istanbul, Turkey;2. Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 06100 Sıhhiye, Ankara, Turkey;3. Hacettepe University, Faculty of Pharmacy, Dept. of Biochemistry, 06100 Sıhhiye, Ankara, Turkey;4. Marmara University, Department of Chemistry, Faculty of Arts and Sciences, 34722 Göztepe, Istanbul, Turkey;1. Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;2. Medicon Pharmaceuticals, Inc., Stony Brook, NY 11790, USA;1. Department of Chemistry, Annamalai University, Annamalainagar 608 002, India;2. Department of Chemistry, TRP Engineering College, Irungalur, Tiruchirappalli 626 126, India;3. Department of Chemistry, Govt. Arts College for Women, Pudukkottai, India;1. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States;2. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA;3. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait;2. Department of Microbiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait;3. Department of Biochemistry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey;2. Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey;3. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey |
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| Abstract: | Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl-2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 ± 0.01 μM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of π-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 Å far from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 µM concentrations. |
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| Keywords: | Asymmetric synthesis of 2,4-oxazolidinediones Monoamine oxidase inhibitory activity Molecular docking Resolution via chiral HPLC Toloxatone |
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